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==Mouse Thymidylate Synthase Cocrystallized with N(4)OHdCMP and Soaked in Methylenetetrahydrofolate== | ==Mouse Thymidylate Synthase Cocrystallized with N(4)OHdCMP and Soaked in Methylenetetrahydrofolate== | ||
<StructureSection load='6f6z' size='340' side='right' caption='[[6f6z]], [[Resolution|resolution]] 2.13Å' scene=''> | <StructureSection load='6f6z' size='340' side='right'caption='[[6f6z]], [[Resolution|resolution]] 2.13Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6f6z]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F6Z OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6f6z]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6F6Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6F6Z FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=NOH:2-DEOXY-N-HYDROXYCYTIDINE+5-(DIHYDROGEN+PHOSPHATE)'>NOH</scene>, <scene name='pdbligand=TGQ:(2~{S})-2-[[4-[[(6~{R})-2-azanyl-4-oxidanylidene-5,6,7,8-tetrahydro-1~{H}-pteridin-6-yl]methyl-methyl-amino]phenyl]carbonylamino]pentanedioic+acid'>TGQ</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=NOH:2-DEOXY-N-HYDROXYCYTIDINE+5-(DIHYDROGEN+PHOSPHATE)'>NOH</scene>, <scene name='pdbligand=TGQ:(2~{S})-2-[[4-[[(6~{R})-2-azanyl-4-oxidanylidene-5,6,7,8-tetrahydro-1~{H}-pteridin-6-yl]methyl-methyl-amino]phenyl]carbonylamino]pentanedioic+acid'>TGQ</scene></td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Tyms ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Thymidylate_synthase Thymidylate synthase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.1.1.45 2.1.1.45] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6f6z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f6z OCA], [https://pdbe.org/6f6z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6f6z RCSB], [https://www.ebi.ac.uk/pdbsum/6f6z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6f6z ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | == Function == | ||
[[ | [[https://www.uniprot.org/uniprot/TYSY_MOUSE TYSY_MOUSE]] Contributes to the de novo mitochondrial thymidylate biosynthesis pathway (By similarity). | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Novel evidence is presented allowing further clarification of the mechanism of the slow-binding thymidylate synthase (TS) inhibition by N(4)-hydroxy-dCMP (N(4)-OH-dCMP). Spectrophotometric monitoring documented time- and temperature-, and N(4)-OH-dCMP-dependent TS-catalyzed dihydrofolate production, accompanying the mouse enzyme incubation with N(4)-OH-dCMP and N(5,10)-methylenetetrahydrofolate, known to inactivate the enzyme by the covalent binding of the inhibitor, suggesting the demonstrated reaction to be uncoupled from the pyrimidine C(5) methylation. The latter was in accord with the hypothesis based on the previously presented structure of mouse TS (cf. PDB ID: 4EZ8), and with conclusions based on the present structure of the parasitic nematode Trichinella spiralis, both co-crystallized with N(4)-OH-dCMP and N(5,10)-methylenetetrahdrofolate. The crystal structure of the mouse TS-N(4)-OH-dCMP complex soaked with N(5,10)-methylenetetrahydrofolate revealed the reaction to run via a unique imidazolidine ring opening, leaving the one-carbon group bound to the N(10) atom, thus too distant from the pyrimidine C(5) atom to enable the electrophilic attack and methylene group transfer. | |||
Molecular Mechanism of Thymidylate Synthase Inhibition by N(4)-Hydroxy-dCMP in View of Spectrophotometric and Crystallographic Studies.,Maj P, Jarmula A, Wilk P, Prokopowicz M, Rypniewski W, Zielinski Z, Dowiercial A, Bzowska A, Rode W Int J Mol Sci. 2021 Apr 30;22(9). pii: ijms22094758. doi: 10.3390/ijms22094758. PMID:33946210<ref>PMID:33946210</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6f6z" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Thymidylate synthase 3D structures|Thymidylate synthase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | |||
[[Category: Lk3 transgenic mice]] | |||
[[Category: Thymidylate synthase]] | [[Category: Thymidylate synthase]] | ||
[[Category: Jarmula, A]] | [[Category: Jarmula, A]] | ||
Latest revision as of 13:01, 12 January 2022
Mouse Thymidylate Synthase Cocrystallized with N(4)OHdCMP and Soaked in MethylenetetrahydrofolateMouse Thymidylate Synthase Cocrystallized with N(4)OHdCMP and Soaked in Methylenetetrahydrofolate
Structural highlights
Function[TYSY_MOUSE] Contributes to the de novo mitochondrial thymidylate biosynthesis pathway (By similarity). Publication Abstract from PubMedNovel evidence is presented allowing further clarification of the mechanism of the slow-binding thymidylate synthase (TS) inhibition by N(4)-hydroxy-dCMP (N(4)-OH-dCMP). Spectrophotometric monitoring documented time- and temperature-, and N(4)-OH-dCMP-dependent TS-catalyzed dihydrofolate production, accompanying the mouse enzyme incubation with N(4)-OH-dCMP and N(5,10)-methylenetetrahydrofolate, known to inactivate the enzyme by the covalent binding of the inhibitor, suggesting the demonstrated reaction to be uncoupled from the pyrimidine C(5) methylation. The latter was in accord with the hypothesis based on the previously presented structure of mouse TS (cf. PDB ID: 4EZ8), and with conclusions based on the present structure of the parasitic nematode Trichinella spiralis, both co-crystallized with N(4)-OH-dCMP and N(5,10)-methylenetetrahdrofolate. The crystal structure of the mouse TS-N(4)-OH-dCMP complex soaked with N(5,10)-methylenetetrahydrofolate revealed the reaction to run via a unique imidazolidine ring opening, leaving the one-carbon group bound to the N(10) atom, thus too distant from the pyrimidine C(5) atom to enable the electrophilic attack and methylene group transfer. Molecular Mechanism of Thymidylate Synthase Inhibition by N(4)-Hydroxy-dCMP in View of Spectrophotometric and Crystallographic Studies.,Maj P, Jarmula A, Wilk P, Prokopowicz M, Rypniewski W, Zielinski Z, Dowiercial A, Bzowska A, Rode W Int J Mol Sci. 2021 Apr 30;22(9). pii: ijms22094758. doi: 10.3390/ijms22094758. PMID:33946210[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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